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spironolactone and licorice = synergistic combination?
I wasn't entirely sure where to put this since it involves both an herb and a synthetic drug, finally decided to put it here.

I came across this study earlier today when I became curious about the possibility of combining these two substances. The idea came to me that both spironolactone and the main active constituent of licorice have their primary actions on the same endocrine pathways. Both are powerful inhibitors of 17-beta-HSD and 17,20 lyase. However, whereas spironolactone is a upregulator of the 11-beta-HSD pathway, it is well known that licorice does the exact opposite and severely inhibits that same pathway... So I thought, hey, what happens if you combine them? The answer:


They cancel each other on their mineralocorticoid activities whilst maintaining their effect on crippling androgens!

Too bad we won't likely be seeing endo's prescribing licorice together with spiro for MtF's any time soon... This study is an amazing discovery if you ask me.

For people who are math challenged, this comes to being that the study participants who had the combination took a combined dose of 100mg spiro and 266mg glycyrrhetinic acid. Assuming an average weight of 68kg for the participants, they took approximately 1.5mg/kg spiro and 4mg/kg glycyrrhetinic acid and had synergy. We don't know if this precise balance is required, just optimal, or even optimal at all... There haven't been any further studies using different doses of spiro and licorice.
Nice find Abi:

Commentary: It’s very useful to find a second study on licorice and it’s role in PCOS. Glycyrrhetinic acid has been shown to reduce serum testosterone and induce regular ovulation. (Yaginuma T, Izumi R, Yasui H, et al. Effect of traditional herbal medicine on serum testosterone levels and its inductions of regular ovulation in hyperandrogenic and oligomenorrheic women. Nippon Sanka Fujinka Gakkai Zasshi 1982;34:939-944) ( Takahashi K, Yoshino K, Shirai T, et al. Effect of a traditional herbal medicine on testosterone secretion in patients with polycystic ovary syndrome detected by ultrasound. Nippon Sanka Fujinka Gakkai Zasshi 1988;789-92.)
Spironolactone is often used as part of a treatment plan in PCOS women with bothersome hirsutism. While Spironolactone can be helpful, fatigue and polyuria are a frequent side effect. It may be that licorice and glycyrrhetinic acid have a potential synergistic effect on the androgen receptors, reduce the side effects associated with Spironolactone, as well as reducing serum testosterone and inducing regular ovulation. Licorice extract along with a lower carbohydrate/higher protein diet, therapies that increase SHBG such as nettles root, green tea, flax seeds and soy and insulin sensitizing strategies such as daily aerobic exercise, fenugreek powder, cinnamon extract, d-pinitol, chromium (and possibly glucophage) offer a comprehensive approach for women with PCOS.

One other side effect from spiro is spasms. A few of us who use spiro have experienced these spasms. I get them on my sides, from what I've been able to find is its related to an electrolyte imbalance.

Quote:The mineralocorticoid antagonist, spironolactone, and its major circulating metabolite, canrenone, also competitively interact with adrenal steroid hydroxylases. In addition, spironolactone is converted by adrenal microsomes to an unknown metabolite which promotes the destruction of cytochromes P-450, decreasing the activities of steroid hydroxylases.

Spiro inhibits DHT (by blocking androgen receptors)
@ 50%
Quote:The mineralocorticoid antagonist, spironolactone, and its major circulating metabolite, canrenone, also competitively interact with adrenal steroid hydroxylases. In addition, spironolactone is converted by adrenal microsomes to an unknown metabolite which promotes the destruction of cytochromes P-450, decreasing the activities of steroid hydroxylases. 

i found this unknown metabolite of spironolactone: 

" 7α-thiospironolactone (SC-24813), a compound which is a potent mineralocorticoid antagonist and which promotes the destruction of adrenal and testicular cytochromes P-450. "

So this means spiro inhibits adrenal and testicular androgens (aka P-450 enzyme family), and I'll bet we'll be able to track it upstream of the CYP17A1 steriodogenisis pathway.
Quote:Licorice is a flavorful substance that has been used in food and medicinal remedies for thousands of years. It is also known as “sweet root,” licorice root contains a compound that is about 50 times sweeter than sugar. It has been used in both Eastern and Western medicine to treat a variety of illnesses ranging from the common cold to liver disease. Licorice affects the endocrine system because it contains isoflavones (phytoestrogens), which are chemicals found in plants that may mimic the effects of estrogen and relieve menopausal symptoms and menstrual disorders. Licorice may also reduce testosterone levels, which can contribute to hirsutism in women.

A small clinical trial published in 2004 by Armanini and colleagues found that licorice root significantly decreases testosterone levels in healthy female volunteers. Women taking daily licorice root experienced a drop in total testosterone levels after 1 month and testosterone levels returned to normal after discontinuation. It is unclear as to whether licorice root affects free testosterone levels (4). The endocrine effect is thought to be due to phytoestrogens and other chemicals found in licorice root, including the steroid glycyrrhizin and glycyrrhetic acid, which also have a weak anti-androgen effect (5, 6).


I wonder just how powerful the effect is. I have seen some herbals that have black licorice derivatives in them.
LR oxidizes NAPDH and inhibits P450 enzymes,  what's more interesting (imo) is the latter part. Meaning I see LR inhibiting aromatase, not potentiating it. Oh sure LR binds to estrogen receptors, but that's where I think it ends. My reasoning is what it isn't doing to the P450 enzyme, (I.e. not synthesizing it). 

I will say this, I have tried spiro/licorice root (though in DGL form) and it's (dgl form) too strong for me. I'm not a big fan of spiro, though I like the fact it's 90% protein bound and goes active in 30-60 minutes with a not so bad half life. But........I believe it's also a partial anti-aromatase (which I had the other way around a few years ago). So,  as you'll see attached " Resihi PDF " clearly states being a dual inhibitor in human tissue,  making it an alternative imo.

(21-11-2014, 04:37 PM)Lotus Wrote:
(15-11-2014, 03:02 AM)Lotus Wrote: What many don't know about phytoestrogens is that in some forms it's stronger than E2- Estradiol, where one can find what's used in HRT. 

Agonistic and antagonistic estrogens in licorice root (Glycyrrhiza glabra)

Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17β-estradiol (E2).

The roots of licorice are a rich source of flavonoids, in particular, prenylated flavonoids, such as the isoflavan glabridin and the isoflavene glabrene. Fractionation of an ethyl acetate extract from licorice root by centrifugal partitioning chromatography yielded 51 fractions. 
One third of the fractions displayed estrogenic activity towards either one or both estrogen receptors (ERs; ERα and ERβ). Glabrene-rich fractions displayed an estrogenic response, predominantly to the ERα. Surprisingly, glabridin did not exert agonistic activity to both ER subtypes. Several fractions displayed higher responses than the maximum response obtained with the reference compound, the natural hormone 17β-estradiol (E2). The estrogenic activities of all fractions, including this so-called superinduction, were clearly ER-mediated, as the estrogenic response was inhibited by 20–60% by known ER antagonists. Most fractions displaying superinduction were rich in flavonoids with single prenylation. Glabridin displayed ERα-selective antagonism, similar to the ERα-selective antagonist RU 58668. Whereas glabridin was able to reduce the estrogenic response of E2 by approximately 80% at 6 × 10−6 M, glabrene-rich fractions only exhibited agonistic responses, preferentially on ERα.

It's very tricky stuff, imo it should only be used under medical supervision. 


Spiro-is also used as a 5ar inhibitor, although not as strong as finasteride or dutas. 

Department of Biochemistry and Molecular Biology, The Ben May Institute for Cancer Research, and The Tang Center for Herbal Medicine Research MC6027, University of Chicago, 5841 S. Maryland, Chicago, IL 60637, USA.

The enzyme steroid 5 alpha-reductase (EC catalyzes the NADPH-dependent reduction of the double bond of a variety of 3-oxo-Delta(4) steroids including the conversion of testosterone to 5 alpha-dihydrotestosterone. In humans, 5 alpha-reductase activity is critical for certain aspects of male sexual differentiation, and may be involved in the development of benign prostatic hyperplasia, alopecia, hirsutism, and prostate cancer. Certain natural products contain components that are inhibitors of 5 alpha-reductase, such as the green tea catechin (-)-epigallocatechin gallate (EGCG). EGCG shows potent inhibition in cell-free but not in whole-cell assays of 5 alpha-reductase. Replacement of the gallate ester in EGCG with long-chain fatty acids produced potent 5 alpha-reductase inhibitors that were active in both cell-free and whole-cell assay systems. Other flavonoids that were potent inhibitors of the type 1 5alpha-reductase include myricetin, quercitin, baicalein, and fisetin. Biochanin A, daidzein, genistein, and kaempferol were much better inhibitors of the type 2 than the type 1 isozyme. Several other natural and synthetic polyphenolic compounds were more effective inhibitors of the type 1 than the type 2 isozyme, including alizarin, anthrarobin, gossypol, nordihydroguaiaretic acid, caffeic acid phenethyl ester, and octyl and dodecyl gallates. The presence of a catechol group was characteristic of almost all inhibitors that showed selectivity for the type 1 isozyme of 5 alpha-reductase. Since some of these compounds are consumed as part of the normal diet or in supplements, they have the potential to inhibit 5 alpha-reductase activity, which may be useful for the prevention or treatment of androgen-dependent disorders. However, these compounds also may adversely affect male sexual differentiation.

The extracts of Ganoderma lucidum inhibited both types of 5 alpha-reductase, a so-called dual inhibition that might be advantageous for the therapy of BPH, since it has been shown that the dual inhibitor dutasteride is more powerful in reducing the DHT plasma concentration than selective type 1 or type 2 inhibitors (Graul et al., 1999)

Anti-androgenic activities of Ganoderma lucidum


Interesting read...however, I'm not much of a chemist...so it's chinese to me lol.  It does however sounds good but for the person taking pharma E anything that is phyto-E will compete for receptors.  I've always been cautious combining the two in fear of loosing the full potential of my meds and wasting my time and money.  Licorice being one..I didn't realize the potential for it being an aa.  I'm just not convinced enough though in it's potentcy for someone to fully transition if that is actually what thier goal is.  Also, the blood pressure delema of licorice root has always been a concern.  I'm still looking into it though for some synergistic way of combining herbals to make my regimen still maximized and not interfering with each other.  I'm still not convinced though.  Albeit, when I only did herbals, I did not fully masculinized after leaving E injectibles.  After 10 years though, testosterone doing its thing even though it was low because of age and maybe the hops and fenugreek influence for so many years.  But still not as effective.  Maybe if I had figured out wp and other natural aa's sooner things may have been different.  But right now, I am dependant on my pharma.  I just would love to get off or keep my dosage of spiro low.  Cant stand the dehydration and cramping if I dont stay on top of my water consumption-1 1/2 u.s gallons of water a day. Thats is an actual requirement.  Less water is guarunteed to cause major problems.  So, to me it's a priority to get off of spiro.
fwiw I can't speak Chinese (Mandarin or Cantonese). The OP was pointing out the discovery of elevating the side effects of spironolactone with LR. Competing with ER's is inconsequential considering how spiro/LR will raise E2 by destroying testicular and adrenal androgens.

Maybe 25mg to 50mg of spiro is an alternative to higher doses?, especially considering how E2 inhibits DHT already too. That's assuming we've already reached the target therapeutic threshold of reduced androgens, imho. Blush

I don't know if I'll keep spiro either tbh, I doubt I even need it. Interestingly, (or oddly) a recent study I saw induced facial hair regrowth in some menopausal women, which I would say our (er, us) hormone levels are somewhat comparable ( re: postmenopasaule women ) . Which makes sense for me because I see faster facial hair regrowth on 100 mg of spiro as to lower amounts (which puzzled me considering I have .3 ng/dL TT (total testosterone) and .5 pg/mL free Testosterone (meaning zero T).

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